title: Evaluation of Lassa antiviral compound ST-193 in a guinea pig model.
abstract: Lassa virus (LASV), a member of the Arenaviridae family, causes a viral hemorrhagic fever endemic to West Africa, where as many as 300,000 infections occur per year. Presently, there are no FDA-approved LASV-specific vaccines or antiviral agents, although the antiviral drug ribavirin has shown some efficacy. A recently identified small-molecule inhibitor of arenavirus entry, ST-193, exhibits submicromolar antiviral activity in vitro. To determine the antiviral utility of ST-193 in vivo, we tested the efficacy of this compound in the LASV guinea pig model. Four groups of strain 13 guinea pigs were administered 25 or 80 mg/kg ST-193, 25 mg/kg of ribavirin, or the vehicle by the intraperitoneal (i.p.) route before infection with a lethal dose of LASV, strain Josiah, and continuing once daily for 14 days. Control animals exhibited severe disease, becoming moribund between days 10 and 15 postinfection. ST-193-treated animals exhibited fewer signs of disease and enhanced survival when compared to the ribavirin or vehicle groups. Body temperatures in all groups were elevated by day 9, but returned to normal by day 19 postinfection in the majority of ST-193-treated animals. ST-193 treatment mediated a 2-3-log reduction in viremia relative to vehicle-treated controls. The overall survival rate for the ST-193-treated guinea pigs was 62.5% (10/16) compared with 0% in the ribavirin (0/8) and vehicle (0/7) groups. These data suggest that ST-193 may serve as an improved candidate for the treatment of Lassa fever.
authors.affiliation: Virology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Cashman
authors.forename: Mark A
authors.initials: MA
authors.lastname: Smith
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Twenhafel
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Larson
authors.forename: Kevin F
authors.initials: KF
authors.lastname: Jones
authors.forename: Robert D
authors.initials: RD
authors.lastname: Allen
authors.forename: Dongcheng
authors.initials: D
authors.lastname: Dai
authors.forename: Jarasvech
authors.initials: J
authors.lastname: Chinsangaram
authors.forename: Tove' C
authors.initials: TC
authors.lastname: Bolken
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Hruby
authors.forename: Sean M
authors.initials: SM
authors.lastname: Amberg
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Hensley
authors.forename: Mary C
authors.initials: MC
authors.lastname: Guttieri
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage*; D001831:Body Temperature; D004195:Disease Models, Animal; D005260:Female; D006168:Guinea Pigs; D007274:Injections, Intraperitoneal; D007835:Lassa Fever / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016019:Survival Analysis; D014766:Viremia / Q000517:prevention & control
chemical_list: D000998:Antiviral Agents